This project will continue work on imaging therapeutic targets to choose appropriate cancer therapy and image the effect of the chosen drug on the therapeutic targets. During the previous funding period we made progress in imaging estrogen receptors (ER) in breast cancer, using [18]F-fluoroestradiol (FES) PET. The renewal will use FES PET to measure regional ER as a pharmaco-dynamic response of breast cancer endocrine therapy and FDG PET to localize active tumor sites and to identify early effects of drug therapy on growth factor pathways including HER2 and ER. We will also extend our imaging of receptor targets to prostate cancer. Aim 1: We will test the use of FES PET to help choose therapy in patients with a history of ER+ breast cancer who have failed prior regimens and are being considered for salvage endocrine therapy. This is a group where our prior experience showed that low FES uptake strongly predicted a lack of response to endocrine therapy. In this same group, we will test whether the use of FES as a predictive marker results in an increased response rate compared to historical data from similar patients where FES imaging was purely observational. Aim 2: Use FES PET and FDG PET to predict response to endocrine treatment combined with other targeted agents. Serial FES/FDG PET will be used to measure the pharmacodynamics (PD) of combined therapy. For patients with ER+ and HER2 over-expressing tumors, imaging will be used to assess the effect of anti-HER2 treatment on ER expression (FES PET) and early response to combined therapy (FDG PET). We will also explore therapy to re-express ER in breast cancer tumors refractory to endocrine therapy using a histone deacetylase (HDAC) inhibitor. FES and FDG PET will be performed prior to therapy and after 14 days of HDAC inhibitor therapy alone, followed by combined HDAC inhibitor/aromatase inhibitor therapy to test the hypothesis that successful therapy can be measured by an increase in ER expression. Aim 3: Develop methods to image hormonal function in prostate cancer. Endocrine therapy continues to be an important first line in prostate cancer patients. We will evaluate androgen receptor-targeted imaging agents, starting with FDHT, but continuing to new agents from project 5 if preclinical trials are encouraging. As in our early studies of ER imaging in breast cancer, the initial focus will be on refining the approaches to image acquisition and analysis, including metabolism and protein binding, and on hormone-refractory disease.